@article{7cc841544dec467d8679f74f59a6bd7b,
title = "Genome instability independent of type I interferon signaling drives neuropathology caused by impaired ribonucleotide excision repair",
abstract = "Aicardi-Gouti{\`e}res syndrome (AGS) is a monogenic type I interferonopathy characterized by neurodevelopmental defects and upregulation of type I interferon signaling and neuroinflammation. Mutations in genes that function in nucleic acid metabolism, including RNASEH2, are linked to AGS. Ribonuclease H2 (RNASEH2) is a genome surveillance factor critical for DNA integrity by removing ribonucleotides incorporated into replicating DNA. Here we show that RNASEH2 is necessary for neurogenesis and to avoid activation of interferon-responsive genes and neuroinflammation. Cerebellar defects after RNASEH2B inactivation are rescued by p53 but not cGAS deletion, suggesting that DNA damage signaling, not neuroinflammation, accounts for neuropathology. Coincident inactivation of Atm and Rnaseh2 further affected cerebellar development causing ataxia, which was dependent upon aberrant activation of non-homologous end-joining (NHEJ). The loss of ATM also markedly exacerbates cGAS-dependent type I interferon signaling. Thus, DNA damage-dependent signaling rather than type I interferon signaling underlies neurodegeneration in this class of neurodevelopmental/neuroinflammatory disease.",
keywords = "Aicardi-Gouti{\`e}res syndrome, ATM, Cerebellum, cGAS/STING, DNA damage, Microglia, Neurodegeneration, Neurodevelopment, Neuroinflammation, RNaseH2",
author = "Aditi and Downing, {Susanna M.} and Schreiner, {Patrick A.} and Kwak, {Young Don} and Yang Li and Shaw, {Timothy I.} and Russell, {Helen R.} and McKinnon, {Peter J.}",
note = "Funding Information: We thank all members of the McKinnon laboratory for their suggestions and comments; we thank Dr. Jingfeng Zhao for genotyping and technical help, the Animal Resource Center, the Small Animal Imaging Center, the Cytogenetics Core, and the Transgenic Core Unit. The Cell and Tissue Imaging Center provided help with microscopy; Flow Cytometry for cell sorting and analysis. P.J.M. is supported by the NIH ( NS-37956 , CA-21765 ), the Cancer Center Support Grant (CCSG) ( P30 CA21765 ), and the American Lebanese and Syrian Associated Charities of St. Jude Children{\textquoteright}s Research Hospital . Funding Information: We thank all members of the McKinnon laboratory for their suggestions and comments; we thank Dr. Jingfeng Zhao for genotyping and technical help, the Animal Resource Center, the Small Animal Imaging Center, the Cytogenetics Core, and the Transgenic Core Unit. The Cell and Tissue Imaging Center provided help with microscopy; Flow Cytometry for cell sorting and analysis. P.J.M. is supported by the NIH (NS-37956, CA-21765), the Cancer Center Support Grant (CCSG) (P30 CA21765), and the American Lebanese and Syrian Associated Charities of St. Jude Children's Research Hospital. A. S.M.D. and P.J.M. conceived and planned experiments and produced the final version of the manuscript. Y.D.K. performed in vivo TOP1cc analysis. S.M.D. T.I.S. and P.A.S. provided bioinformatics analysis of RNA-seq experiments. A. and Y.L. performed histology, immunostaining, and tissue collection. A. and H.R.R. generated the mutant mouse models and performed additional experiments. All authors contributed to editing and completion of the manuscript. The authors declare no competing interests. Publisher Copyright: {\textcopyright} 2021 Elsevier Inc.",
year = "2021",
month = dec,
day = "15",
doi = "10.1016/j.neuron.2021.09.040",
language = "English (US)",
volume = "109",
pages = "3962--3979.e6",
journal = "Neuron",
issn = "0896-6273",
publisher = "Cell Press",
number = "24",
}